Somatic point mutations in the active site of isocitrate dehydrogenase (IDH) 1 and 2 are found in multiple tumors. Enasidenib is a potent and selective inhibitor of the mutant IDH2. It inhibits the production of oncometabolite (R)-2-hydroxyglutarate (2HG) by the IDH2R140Q homodimer, the IDH2R140Q/WT heterodimer, and the IDH2R172K/WT heterodimer with IC50 values of 0.1, 0.03, and 0.01μM, respectively. Enasidenib also displayed time-dependent potency for inhibiting the canonical forward (oxidative) reaction in the IDH2WT homodimer with an IC50 value of 1.8μM. Moreover, Enasidenib inhibited 2HG production in HCT-116 KI (IDH2R172K, TF-1 pLVX (IDH2R140Q), TF-1 pLVX (IDH2R172K), U87MG pLVX (IDH2R172K), U87MG pLVX (IDH2R140Q) cell lines with IC50 values of 0.53, 0.02, 0.98, 1.59, and 0.01μM, respectively. In the presence of 0.1μM enasidenib, IDH2R140Q cells exhibited an approximately 50% decrease in intracellular 2HG and an increase in the percentage of cells expressing cell surface markers associated with granulocytic differentiation. Incubation of IDH2R140Q blast cells with 5μM enasidenib for 8 days significantly increased the number of cells with multilobed nuclei when compared with control cells. In tumor-bearing mice, two doses of 25 mg/kg enasidenib given 12h apart resulted in 99.2% inhibition of 2HG production in tumors. In a mouse xenograft model of primary human AML, administration of enasidenib (30 mg/kg, twice daily) for 38 days reduced serum and intracellular 2HG levels compared to vehicle-treated group[2].
作用机制
AG-221 inhibits IDH2 by allosterically stabilizing its open homodimer conformation, thereby preventing the conformational change required for catalysis[2].
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